Parasiticide



Patented Oct. 26, 1937 UNITED STATES PATENT OFFICE D. Jayne & Son, Inc.,

poration of Delaware No Drawing.

Wilmington, Del., a cor- Application June 13, 1935,

Serial No. 26,521

1 Claim.

This invention relates to parasiticides, more particularly to new and improved compositions adapted to effect the removal of internal animal parasites from host animals, including man. Animal parasites is here defined as all parasitic organisms exclusive of plants and bacteria.

It is known that amebas, worms and other protozoa and metazoa infest the gastro-intestinal tract as well as other sites in the body. Numerous preparations designed to kill or eliminate such parasites have been proposed, these being known as amebicides, anthelmintics, or in general, parasiticides. A number of such preparations have met with success, but they have been highly specific in their action in the sense that only a limited group or even only one species in a group of parasites is affected. Moreover most of these have been shown to be highly toxic to the host. Probably two of the best known remedies heretofore used are oil of Chenopodium (active component, ascaridole) and tetrachlorethylene.

The term vermicide is used in the claims to designate the compositions and the remedial effects contemplated by this invention and referred to in this application. The term vermicide is used in its accepted meaning and can be defined as an anthelmintic drug or medicine destructive to intestinal animal parasites. Such parasites, specifically, are those referred to above and include but are not limited to those mentioned specifically in the description of this application.

With a view to advancing the development of the art of parasiticides, researches have been conducted resulting in the inventions and discoveries set forth in the following specification.

It is an object of the invention to provide new and improved antiparasitic compounds. One improvement in view is that new remedies shall be less specific in their application than those hitherto proposed. Since the parasites envisaged in this invention exist in environments practically free of oxygen and are harmfully aifected by oxygen in certain active forms, the desired generality of the drug effect is aimed to be accomplished by the application of remedies supplying oxygen in suitable form and amount. The invention, then, has for its further objects the use of new and improved antiparasitic compounds containing oxygen in such suitable form, and particularly organic peroxides. Further objects are specifically included in the particular compounds set forth in this specification.

The compounds found to be particularly useful according to the present invention are organic peroxides, which term is to be understood to include derivatives of hydrocarbons containing the peroxide (O2fl) group, which derivatives may in addition contain other substituent groups or 5 elements commonly found in organic compounds, such as hydroxyl (OH), iodine (I), carboxyl (COzH), oxide (-O) etc.

The use of oil of Chenopodium has been established as an eflicient antiparasitic remedy in in- 10 festations of human beings and lower animals. The remedial effect of this oil has been shown to be due to the organic peroxide, ascaridole, which it contains.

CHa

C{(L\CH| H 1/ H: .CH:

orn

It is probable that the therapeutic effect of ascaridole is due, in part at least, to the peroxide group which it contains. This compound however contains other important groupings; name- .ly, the olefin linkage and the para-menthene structure. Possibly because of these latter structural units this peroxide is quite toxic for human beings and lower animals. The use of Chenopodium oil is unsafe in view of its high toxicity when administered in doses sufficiently large and frequent to produce its anti-parasitic effect. This inventionhas for one of its objects the therapeutic use of organic peroxides, as above described, with much reduced toxicity for the host. This can be obtained by the preparation and bioassay of many peroxide compounds with or without substituent groups. I have studied some other peroxides as anthelmintics and have found these to be superior therapeutic agents.

As an approach to the solution of this question, the action of hydrogen peroxide and of disuccinyl peroxide has been studied, with particular reference to Ascaris lumbricoides, and these substances have been found to be very toxic to the parasites. (J. Am. Pharm. Assn. vol. IQUII, #11, November 1934) This indicates that the peroxide group, or the hydrogen peroxide or nascent oxygen therefrom under various conditions, has in itself pronounced anthelmintic properties. In view'of these findings, researches have been extended to the utilization of other peroxides with a view to finding those that have the desired property of low toxicity,,f or the human It was found that diheptanol peroxide killed Ascaris lumbricoides readily in the beaker and that dogs were freed of all Tozocara canis which they had harbored by treatment with this peroxide. By assaying diheptanol peroxide for anthelmintic efliciency and toxicity for the host upon a large number of dogs and conducting simultaneously the same. experiments with Chenopodium oil, we have shown that the ratio of anthelmintic efliciency to toxicity is much higher for diheptanol peroxide than for Chenopodium oil, and therefore that diheptanol peroxide is a better drug for this parasitic disease, ascariasis.

And yet it must be emphasized that in all probability further search among synthetic organic peroxides will reveal compounds with remedial properties even superior to those of diheptanol peroxide.

A typical example of a bioassay with Asoafis lumbricoides is as follows:

Bioassay The efiect of the anthelmintic activity toward Ascaris lumbricoides was determined by immersion of vigorous specimens in a solution or emulsion of the substance being tested. The apparatus was a rectangular aquarium with glass windows which was filled with water and served as a constant temperature bath. The temperature was maintained between 37 C. and 38 C. The aquarium was provided with a metal cover conworms were 22-24 cm. in length and weighed 2.0-2.35 gms. They were A. lumbricoides obtained from the intestines of swine. Observation was made of the number of minutes after immersion required to produce cessation of movement, paralysis and death and were conducted at hourly intervals for a period of five hours.

In general, it is found that organic compounds containing a peroxide group are effective as anthelmintics in the beaker tests described. These tests have shown that hydrogen peroxide, disuccinyl peroxide, diheptanol peroxide were all very toxic to the round worm, Ascaris lumbricoides. In using the term peroxide group" it is to be understood that this includes substances containing the OO linkage or tautomeric modifications thereof. A general formula for such a composition would be R10.0R2 where R1, R2 are either hydrogen or a hydrocarbon radical or a derivative thereof. In addition to antiparasitic effect the therapeutic peroxide must have suflicient chemical stability to reach the site of infestation and to remain there for a suflicient period to exert the antiparasitic action. This requirement renders hydrogen peroxide and some organic peroxides such as some of those containing the and linkages unsuitable because these decompose too readily in the presence .of water and body fluids. For the therapeutic experiments, therefore, I chose diheptanol peroxide since this has a high degree of stability as shown by its passage through the gastrointestinal tract of dogs little altered in shape or amount while at the same time ridding the dog of all the worms present. Diheptanol peroxide is, therefore, included here as an example of a suitable therapeutic compound.

Therapeutic experiments with reference to diheptanol peroxide show the following results in canine ascariasis:

Turn I Percentage of worms removed Dose Dru No.0! Worms Worms Percent animals preeent removed removed (s-I e-) 0.2 e 129 48 37 as 2 25 22 as 1.0 a 13s 12s 03 Tenn: 11

Rate of elimination of worms before and after treatment with diheptanol peroxide Rate eliminated Dose Cure (w No. of worms eliminated Do: No.

(31kg) (Percent) Before After Before Alter Autopsy 161 1. 02 10a 0. 2 14. 0 1 l4 0 N 0. :0 10a 0 0. 2 13. 0 2 l7 0 taining holes which supported 400 cc. beakers. Five worms were placed in each beaker which contained 300 cc. of solution or emulsion. The

Diheptanol peroxide was administered in solid form in gelatin capsules. The animals were observed for periods of seven to ten days prior to 2,097,114 treatment and the rate of elimination of worms observed over this period. After treatment they were observed for varying periods of time and then sacrificed. The number of worms passed during life and found at autopsy were observed. The two tables above show (1) the percentage of total worms present eliminated by the treatment as observed with a large number of dogs, and (2) the diflerence in rate of elimination of parasites before and after treatment. All experiments carried out consisted of one dose treatments, the diheptanol peroxide being given without solvents and without any other medicaments such as laxatives.

Experiments have been conducted to assure that effective doses of diheptanol peroxide can be tolerated by the infested animals. The therapeutic dosage of diheptanol peroxide was found to'be between 0.3 and 1.0 g/kg. and laboratory data revealed that from 15 to 5 times this dosage respectively was easily tolerated by the dog. In fact; toxic effects from this material upon the host have never been observed and therefore a maximum tolerated dose cannot be stated at this time. Higher doses were not given because of the mechanical difliculties involved in administering such quantities with a one-dose technique. However, one dog showed no symptoms of intoxication on receiving five doses of 3.0 g./kg. each at short intervals. Moreover it is likely that the administration of diheptanol peroxide in a suitable solvent would show that less than the dose rate of 0.3-1.0 g./kg. would be therapeutically efiective. These results show the suitability and safety of 'diheptanol peroxide as a drug and hence indicate its superiority to Chenopodium oil. The therapeutic index (rate of maximum tolerated dose to minimum therapeutic dose) in dogs was found to be 8.0 for Chenopodium oil, while the above data show that this index for diheptanol peroxide is at least 15.0 and is probably much higher.

Having thus described the invention and the therapeutic application thereof, I claim: I

A vermicide adapted forinternal administration, comprising diheptanol peroxide (CH3) (CH2) 5CHOH-OO-CHOH(CH2) sCHs LEWIS W. 31112. 

